Untreated gestational diabetes mellitus (GDM) is associated with an increased risk of complications for both mother and child. Many of these complications can be reduced by early diagnosis and treatment of GDM. However, worldwide there is a lack of agreement on the best way to diagnose and treat GDM.

In the Netherlands, the Dutch Society of Obstetrics and Gynaecology guideline “Diabetes and Pregnancy” for the screening and treatment of GDM was implemented in 2010. The diagnostic thresholds are based on the old WHO consensus originating from 1999 and have until now not been updated to the newest (more stringent) criteria, implemented in 2013. These new criteria have been adopted by many expert committees. However, evidence that applying the stricter criteria for GDM improves pregnancy outcomes is limited.

The research described in this thesis aimed to evaluate the current Dutch national guideline of GDM i.e. what is the outcome of GDM pregnancies using this guideline? And what are consequences when the current diagnostic criteria of GDM are to be revised?

In this thesis we have shown that the currently used national guideline for screening and treatment of GDM is successful in reducing the risk of short-term adverse outcomes, but not in reducing the likelihood of having a large-for-gestational-age neonate. We have also shown that the long-term care for GDM is far from optimal and requires further improvement. In order to further optimize GDM care and pregnancy outcomes we advise the use of more stringent blood glucose criteria for GDM diagnosis.

Abstract
Background: Early diagnosis and treatment of high blood pressure (BP) and cholesterol is important to reduce cardiovascular risk. We compared BP and LDL-cholesterol (LDL-C) as well as the quality of treatment between obese subjects and normal weight and overweight individuals.
Methods: 87,648 participants of the Lifelines study were categorised according to obesity (normal weight/ overweight/obesity) and age. Mean systolic BP and LDL-C were calculated depending on treatment, BMI, age and sex.
Results: In all age groups, except those aged 70-80 years, women had a significantly lower BP than men. Use of BP-lowering medication did not result in BP levels comparable with non-users, except in those aged 70-80 years. Despite medication, the BP was insufficiently controlled in 20-50% of participants. BP was significantly higher in obese vs. normal weight and overweight individuals of all ages, but most apparently in men younger than 50 years. Mean LDL-C varied between 2.5- .0 mmol/l. Despite higher statin use, obese participants had a higher LDL-C than those with a normal weight. Statins abolished the age-dependent LDL-C increase. Many participants did not achieve target LDL-C < 2.5 mmol/l. A small percentage of individuals treated with BP-lowering drugs were also using statins (overall 32% in men, 17% in women).
Conclusion: Obese individuals, especially men younger than 50, have a higher BP and LDL-C compared with those with overweight and a normal weight. Use of BP-lowering drugs did not revert the BP back to levels normal for the specific age and BMI group, whereas statins abolished the age-related increase in LDL-C. These data suggest that more attention is needed for active screening and treatment of cardiovascular risk factors.

Abstract
Introduction and aim: Insight into the total economic burden of diabetes mellitus (DM) is essential for decision makers and payers. Currently available estimates for the Netherlands only include part of the total burden or are no longer up-to-date. Therefore, this study aimed to determine the current total economic burden of DM and its complications in the Netherlands, by including all the relevant cost components.
Methods: The study combined a systematic literature review to identify all relevant published information and a targeted review to identify relevant information in the grey literature. The identified evidence was then combined to estimate the current total economic burden.
Results: In 2016, there were an estimated 1.1 million DM patients in the Netherlands, of whom approximately 10% had type 1 and 90% had type 2 DM. The estimated current total economic burden of DM was € 6.8 billion in 2016. Healthcare costs (excluding costs of complications) were € 1.6 billion, direct costs of complications were € 1.3 billion and indirect costs due to productivity losses, welfare payments and complications were € 4.0 billion.
Conclusion: DM and its complications pose a substantial economic burden to the Netherlands, which is expected to rise due to changing demographics and lifestyle. Indirect costs, such as welfare payments, accounted for a large portion of the current total economic burden of DM, while these cost components are often not included in cost estimations. Publicly available data for key cost drivers such as complications were scarce.

Overweight and obesity often lead to the development of a disturbed glucose metabolism, increased blood pressure and a disturbed fat profile (too low values of the “good” HDL-cholesterol and high triglycerides values). This combination of metabolic complications is called the metabolic syndrome. It is associated with an increased risk of type 2 diabetes and cardiovascular diseases. Approximately one in four Europeans have the metabolic syndrome. Even though it is usually caused by obesity, a sub-group of obese people seem to be less susceptible to the metabolic health risks. They have an equally healthy metabolism as lean people. In the literature, this is referred to as metabolically healthy obese.

In ten large population studies from seven different European countries the occurrence of the metabolic syndrome and metabolically healthy obesity has been estimated. The metabolic syndrome is common in Europe and the Netherlands. However, in the Dutch LifeLines study still nearly 1 out of 4 obese women and 1 out of 10 obese men are metabolically healthy (depending on their age). From studies with LifeLines data only, it seems that smoking-, drinking-, eating- and exercise behaviours of these people is important. The level of tobacco use and drinking more than one alcoholic beverage per day was already related to the development of the metabolic syndrome. However, a ‘healthy’ dietary pattern and intensive vigorous physical activity increased in obese people the chance of metabolically healthy obesity. Actively changing lifestyle factors will reduce the number of people developing the metabolic syndrome, and consequently will reduce the incidence of type 2 diabetes and cardiovascular diseases. However, even before these more serious chronic conditions occur, obese subjects (without metabolic complications) had an impaired quality of life. Therefore, in the treatment of obesity it is advisable to take into account aspects relating to the quality of life.

The first part of this thesis describes the role of cholesterol particles and associated proteins, and their role in the development of cardiovascular disease. There seems to be an advantage in determining the balance between good and bad cholesterol, as compared to the separate measures when attempting to predict the development of cardiovascular disease. Certain genes that have an influence on proteins transporting cholesterol from one particle to the other, do not seem to have an effect on the predictive value of these measures. The inhibition of this protein does increase the level of the good cholesterol, but this does not seem to result in any survival benefit.

The second part of this thesis describes the effect of cholesterol lowering agents on different cholesterol particles and associated proteins. Cholesterol lowering agents seem to affect the number of particles less than their cholesterol content. This could lead to a lack of intensive cholesterol treatment when only the cholesterol concentration is considered.

For more information: http://www.rug.nl/research/portal/en/publications/lipids-and-apolipoproteins-in-cardiovascular-disease(431d2a57-3e66-4136-bfff-0198e09914d7).html

Thyroid cancer is increasingly common. This is especially the case for differentiated thyroid cancer (DTC), which has a favorable prognosis. Treatment consists of surgical removal of the thyroid gland, radioiodine treatment, and life-long administration of relatively high doses of thyroid hormone. This treatment is effective, but also rather aggressive since it can result in the occurrence of both short- and long-term adverse effects. There used to be little attention for this issue, as cancer-related outcome was less favorable. Nowadays, we see a lot of DTC patients with small tumors who have a near-normal life expectancy. For these patients long-term adverse effects of treatment are very important since they can negatively impact quality of life.

In this thesis we therefore studied the occurrence of long-term effects of DTC treatment. We found that atrial fibrillation (a cardiac rhythm disturbance) and mortality due to cardiovascular diseases are more common in DTC patients as compared to the general population. Furthermore, we found that a part of patients have salivary glands dysfunction following radioiodine treatment. Fortunately, the adverse effects of treatment on bone marrow function were limited.

Furthermore, there is a small group of thyroid cancer patients with more aggressive disease. For these patients, cure is often not achievable. Therefore, we studied the efficacy and toxicity of tyrosine kinase inhibitors (a new class of drugs) that have been studied in these patients. In addition, we studied the hereditary material of several thyroid cancers in an attempt to understand more of thyroid cancer pathogenesis.

For more information: http://www.rug.nl/research/portal/en/publications/thyroid-cancer-treatment(c182a5fa-f154-459e-ad70-1c137df8c142).html

Abstract
Objective: To evaluate the cost-effectiveness of exenatide twice daily (BID) versus bolus insulin lispro three times daily (TID) as add-on therapy when glycemic control is suboptimal with titrated basal insulin glargine and metformin.
Methods: The analysis was based on the recent 4B Study, which compared exenatide BID and lispro TID as add-on therapies in subjects with type 2 diabetes insufficiently controlled despite titrated insulin glargine. The Cardiff Diabetes Model was used to simulate patient costs and health benefits beyond the 4B Study. The Swedish healthcare perspective was adopted for this analysis; costs are reported in €EUR to aid interpretation. The main outcome measure was the cost per quality-adjusted life-year (QALY) gained with exenatide BID compared to lispro TID.
Results: Exenatide BID was associated with an incremental cost of €1,270 and a QALY increase of +0.64 compared with lispro TID over 40 years. The cost per QALY gained with exenatide BID compared with lispro TID was €1,971, which is within conventional limits of cost-effectiveness. Cost-effectiveness results were generally robust to alternative assumptions and values for key model parameters.
Limitations: Extrapolation of trial data over the longer term can be influenced by modelling and parameter uncertainty. Cost-effectiveness results were generally insensitive to alternative values of key model input parameters and across scenarios.
Conclusions: The addition of exenatide BID rather than insulin lispro to basal insulin is associated with similar or better clinical outcomes. Illustrated from the Swedish healthcare perspective, analysis with the Cardiff Diabetes Model demonstrated that exenatide BID represents a cost-effective treatment alternative to lispro TID as add-on therapy in type 2 diabetes patients insufficiently controlled on basal insulin.